Inflammatory Bowel Disease (IBD) is the general name for diseases that cause inflammation in the small intestine and colon and usually relates to three gastrointestinal disorders of unknown etiology, namely, ulcerative colitis, Crohn's disease, and indeterminate colitis. They have many symptoms in common with irritable bowel syndrome, including abdominal pain, chronic diarrhea, weight loss, and cramping which makes the definitive diagnosis extremely difficult. Ulcerative colitis, also referred to as UC, is the most common inflammatory bowel disease and affects various portions of the gastrointestinal tract (GI), particularly the lower GI tract, and more particularly the colon and/or rectum. Almost without exception, UC starts involving the rectum before it spreads proximately to contiguous portions or to the entire colon. The disease activity is usually intermittent, with relapses and periods of quiescence. In mild UC, the colonic mucosa appears hyperaemic and granular, wherein in more severe cases, tiny punctuate ulcers are present and the mucosa is characteristically friable and may bleed spontaneously. Crohn's disease predominates in the small and the large intestine. Diseased patients usually have deeper inflammations in the most distal part of the small intestine and the first part of the large intestine (ileocaecal region), but the inflammation can be located in any part of the gastrointestinal tract.
It is now well documented that such diseases are also usually associated with an increased risk of subsequent gastrointestinal cancer, especially colorectal cancer, and eventhough the mechanisms are not yet proven, pathways which could lead to subsequent transformation, heightened proliferation and malignant invasion occurring during multiple acute inflammatory episodes, are disclosed in patent application WO 95/18622. In this context, it is appropriate to seek for efficient methods of treatment of IBD.
Up to the present days, existing drug therapies cannot cure IBD, but tend to reduce as much as possible the intestinal inflammation. Existing treatments basically depend on the seriousness of the illness, which might sometimes lead to surgical removal of the diseased colon. For ulcerative colitis, most people are treated for life with medication containing aminosalicylates, such as 5-aminosalicylic acid (5-ASA), or 4-aminosalicylic acid (4-ASA) to help control the inflammation. 5-ASA is chemically related to aspirin and has the same analgesic, antipyretic and anti-inflammatory properties. It is part of the Non Steroidal Anti Inflammatory Drugs (NSAID) and has been used for years in the treatment of Crohn's disease and especially for Ulcerative Colitis where it markedly reduces the chance of a flare up. Different suitable derivatives containing aminosalicylates have already demonstrated their efficacy and are presently on the market. For instance, sulfasalazine contains 5-ASA and sulfapyridine which role is to help carrying the anti inflammatory drug to the intestine.
Increased leukocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites (particularly leukotriene B4), and increased free radical formation in the inflamed intestinal tissue are all present in patients with Inflammatory Bowel Diseases. Oral or local administration of 5-ASA allows the drug to act locally on the diseased area as it is absorbed by colonic and intestinal epithelial cells where its effectiveness depends on the mucosal concentration, by inhibiting leukocyte chemotaxis, decreasing cytokine and leukotriene production, and scavenging free radicals. A description of the mechanisms of action as well as a review of effective dosages are disclosed in Campieri, et al., “Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis”, Gut, 1991(8) pp 929-931, and Wallace J. L., et al., “Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease”, Gastroenterology, 1989. 96(1): pp 29-36.
Prednisolone, ((11β)-11,17,21-trihydroxypregna-1,4-diene-3,20-dione), is a synthetic corticosteroid that is of significant importance in the treatment of inflammatory diseases. It is disclosed in U.S. Pat. No. 3,134,718 and in general, is known to be efficient in the treatment of inflammatory and immune diseases. Indeed, the sodium phosphate salt of prednisolone is known to be used to treat a vast array of conditions including: allergic states, dermatologic diseases, endocrine disorders, neoplastic disorders, and rheumatic disorders while the acetate salt is known for use in ophthalmic preparations. Products are now currently available on the market in oral dosage forms such as in Cortancyl® (prednisolone acetate) or Medrol® (methylprednisolone), as well as in enemas such as in Predsol® (prednisolone sodium phosphate).
The prednisolone metasulfobenzoate (PMSB) is also already known. It is currently commercially available in its sodium salt form such as in the Solupred®, or Predocol® products and several controlled release oral forms comprising PMSB are disclosed, as in WO 2003/68196 for example.
In addition, further improvements in the research of new IBD drug treatments have led to the development of new steroid drugs such as tixocortol pivalate, fluticasone propionate, beclomathasone dipropionate and budesonide, which appeared to be a highly potent topical glucocorticosteroid. Specific combinations of these drugs are known, such as in WO 00/24388 which discloses examples of combinations of budesonide with 5-ASA that are useful for the treatment of IBD.
However, whereas improvements in the state of the art are usually directed to galenic considerations in order to locate the delivery of the active ingredients at the specific sites of adsorption, the efficacy of the existing forms remain however limited by the physical properties and therapeutical potency of the active ingredient that are used. Because PMSB is easily degraded, there is a need to provide improved compositions that would provide a higher therapeutical utility.
It has been surprisingly found that PMSB or its pharmaceutically acceptable salts thereof in combination with 5-ASA, derivatives or pharmaceutically acceptable salts thereof resulted in highly stable formulations that were useful in the treatment of IBD. Also, it has been surprisingly found that the combination of these two active ingredients resulted in composition having synergic effects.